Is FH p.Pro13Ser (c.37C>T) pathogenic?

FH p.Pro13Ser (c.37C>T) is classified Uncertain significance in FH (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.1006); Very rare (popmax 0.00245%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with FH p.Pro13Ser (c.37C>T)?

FH p.Pro13Ser (c.37C>T) is associated with hereditary neoplastic syndrome, fumaric aciduria (ClinVar).

How common is FH p.Pro13Ser (c.37C>T) in the general population?

FH p.Pro13Ser (c.37C>T) is very rare (popmax 0.00245%, eas) (gnomAD).

What do computational predictors say about FH p.Pro13Ser (c.37C>T)?

AlphaMissense predicts likely benign (score 0.1006) — an in-silico prediction, not a clinical call.

FH p.Pro13Ser

c.37C>T · rs587778360 · VCV231067

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1006 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00245%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1006	likely benign
REVEL	0.33	indeterminate
SaProt	LLR -6.63	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.88	GERP -2.4
Regional constraint	o/e 1.12	unconstrained · MANE · 6,014 bp · p 0.17 · regional, not allelic
Overall
CADD	5.188	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00245% East Asian · 1/40,846 alleles

Filtering AF 0.000254% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000163%

Overall 0.000517% 8/1,547,044 alleles · very rare exomes 7/1,394,802 · genomes 1/152,242 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00245%	40,846
European (non-Finnish)	0.000611%	163,716

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: FH
Protein: p.Pro13Ser
Coding: c.37C>T
MANE Select: NM_000143
dbSNP: rs587778360
Type: single nucleotide variant
Location: chr1:241519686 (GRCh38)
Gene constraint: LOEUF 0.599 · pLI 0.27 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 92.92 · 8 PDB

Full FH gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: fumaric aciduria

Similar variants

FH p.Pro13Ala Uncertain significance ★★ ⚠ same residue
FH p.Pro13Leu Uncertain significance ★★ ⚠ same residue
FH p.Pro13= Likely benign ★★ same residue
FH p.Pro13Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
FH p.Pro13Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
FH p.Pro13Val Uncertain significance ★ same residue
FH c.1108+1G>T Pathogenic/Likely pathogenic ★★ same condition
FH c.1236+1G>A Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/fh-p-pro13ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown